Drug-Induced Inhibition of Angiotensin Converting Enzyme and Dipeptidyl Peptidase 4 Results in Nearly Therapy Resistant Bradykinin Induced Angioedema: A Case Report

Abstract

Objective:Unusual clinical course Background:Bradykinin is an underestimated mediator of angioedema. One subgroup of bradykinin induced angioedema is angioedema triggered by treatment with angiotensin converting enzyme (ACE) inhibitors. Due to its localization in the head and neck region and its unpredictable course, it is a possibly life-threatening condition. There is not an officially approved treatment for ACE inhibitor induced angioedema. Case Report:We present a case of an 83-year-old woman, who presented to our ENT department because of acute swelling of the tongue. On admission, there was no pharyngeal or laryngeal edema and no dyspnea. Treatment with glucocorticoids and antihistamines had no response. The patient had ramipril as regular medication, so we assumed ACE inhibitor induced angioedema and treated consequently with C1-inhibitor (human) 1,500 IU. Nevertheless, swelling was progressive and required intubation. Even after the second specific treatment with icatibant, her angioedema subsided extremely slowly. The patient also had regular treatment with saxagliptin, a dipeptidyl peptidase 4 inhibitor, so we assumed that the simultaneous inhibition of two bradykinin degrading enzymes led to a treatment-refractory course of angioedema. Conclusions:General awareness for bradykinin induced angioedema due to regular medication is limited. Our case demonstrated the importance of improving awareness and knowledge about this side effect. We need a better understanding of the pathomechanism to aid in more precise clinical diagnosis. Securing the patient's airway as well as administration of an officially approved therapy is of utmost importance. As the number of patients simultaneously treated with antihypertensive and antidiabetic drugs is likely to increase, the incidence of bradykinin mediated drug induced angioedema is likely to increase as well.

Differences and Similarities in the Mechanisms and Clinical Expression of Bradykinin-Mediated vs. Mast Cell–Mediated Angioedema

“…Indeed, patients with ACEi-AE have been reported to have increased plasma BK levels. Dipeptidyl peptidase-4 inhibitors (DPPIV) or neprilysin (neutral endopeptidase) inhibitors used in the treatment of hypertension can increase the propensity of drug-induced angioedema significantly when combined with ACEi [ 36 – 38 ].…”

Angioedema associated with dipeptidyl peptidase-IV inhibitors

“…In particular, angioedema was observed in four patients treated with ACEIs and gliptins [sitagliptin (n = 3) and saxagliptin (n = 1)] [ 37 , 40 – 42 ] and recovered or markedly improved after discontinuation of both drugs [ 37 , 41 ] or disappeared after the interruption of the ACEI alone [ 40 ], whereas in one case treatment changes were not specified [ 42 ]. In two of the cases managed with discontinuation of both drugs [ 37 , 41 ], the ACEI alone was initially withdrawn but the attacks persisted even after this change.…”

Case Report: Compromised Airway Following Anesthesia and Its Correlation With the Use of ACE Inhibitors—An Unexpected Clinical Event and Review of Literature

“…ACEI-IA is a rare side effect (0.2–0.5%), but the large number of people taking these medications makes it the leading cause of drug-induced angioedema ( 5 ). The incidence is underestimated as many physicians misdiagnosed it as an anaphylactic reaction, which delays the diagnosis, leading to poor initial management, deleterious to the patient ( 6 ). Possible risk factors include female gender, black race, previous history of angioedema, smoking, seasonal allergies, recent initiation of ACE-I, and immunosuppression ( 4 ).…”